Microbial secondary metabolites (MSMs) have played and continue to play a highly significant role in the drug discovery and development process. Genetically, MSM chemical structures are biologically synthesized by microbial gene clusters. Recently, however, the speed of new bioactive MSM discovery has been slowing down due to consistent employment of conventional cultivation and isolation procedure. In order to alleviate this challenge, a number of new approaches have been developed. The strategy of one strain many compounds (OSMAC) has been shown as a simple and powerful tool that can activate many silent biogenetic gene clusters in microorganisms to make more natural products. This review highlights important and successful examples using OSMAC approaches, which covers changing medium composition and cultivation status, co-cultivation with other strain(s), adding enzyme inhibitor(s) and MSM biosynthetic precursor(s). Available evidences had shown that variation of cultivation condition is the most effective way to produce more MSMs and facilitate the discovery of new therapeutic agents.

alpha-Glucosidase (AGS) inhibitors have been regarded as an ideal target for the management of type 2 diabetes mellitus (T2DM) since they can maintain an acceptable blood glucose level by delaying the digestion of carbohydrates and diminishing the absorption of monosaccharides. In the process of our endeavor in mining AGS inhibitors from natural sources, the culture broth of two mangrove-derived actinomycetes Streptomyces sp. WHUA03267 and Streptomyces sp. WHUA03072 exhibited an apparent inhibitory activity against AGS. A subsequent chemical investigation into the two extracts furnished 28 secondary metabolites that were identified by spectroscopic methods as two previously undescribed linear polyketides 1-2, four benzenoid ansamycins 3-6, fourteen cyclodipeptides 7-18, one prenylated indole derivative 19, two fusicoccane-type diterpenoids 20-21, two hydroxamate siderophore 22-23, and five others 24-28. Among all of the isolates, 11 and 24 were obtained from actinomycetes for the first time, while 20-21 had never been reported to occur in a marine-derived microorganism previously. In the in vitro AGS inhibitory assay, compounds 3, 8, 9, 11, 14, 16, and 17 exhibited potent to moderate activity with IC50 values ranging from 35.76 ± 0.40 to 164.5 ± 15.5 muM, as compared with acarbose (IC50 = 422.3 ± 8.4 muM). The AGS inhibitory activity of 3, 9, 14, 16, and 17 was reported for the first time. In particular, autolytimycin (3) represented the first ansamycin derivative reported to possess the AGS inhibitory activity. Kinetics analysis and molecular docking were performed to determine the inhibition types and binding modes of these inhibitors, respectively. In the MTT assay, 3, 8, 9, 11, 14, 16, and 17 exhibited no apparent cytotoxicity to the human normal hepatocyte (LO2) cells, suggesting satisfactory safety of these AGS inhibitors.

This chemical study reports a novel siderophore-like compound, beta-cyclopiazonic acid (1, beta-CPA) extracted from marine fungus Aspergillus flavus. The chemical structure of beta-CPA was elucidated by a combination of extensive spectroscopic analyses and TDDFT-ECD calculations. The iron-binding ability and CAS assays demonstrate that beta-CPA is a novel siderophore that features a different chemical structure from those of traditional siderophores. The beta-CPA has no obvious influence on the growth of bacterium Pseudomonas aeruginosa PAO1. However, its iron chelator could promote the growth of P. aeruginosa PAO1, suggesting that P. aeruginosa employed siderophores to sequester iron, which is vital for their survival. The study provides the physiochemical evaluation of beta-CPA, an unusual skeleton-structure siderophore, which for the first time, was proven to have the ability to bind iron and affect P. aeruginosa growth. This new discovery of siderophore provides an opportunity for developing novel anti-P. aeruginosa drugs.

For nonlinear uncertain switched systems, the problem of how to overcome the controller vulnerability is studied when the actuator saturation is considered. The sufficient condition for guaranteeing nonfragile robust exponential stabilization of the system is derived by using the method of minimum dwell time. Then, a switching law and the nonfragile state feedback controllers are designed such that the closed-loop system can be robustly exponentially stabilized at the origin. Next, when some scalar parameters of the closed-loop system are given, the design issue of the nonfragile state feedback controllers, which aim at enlarging the estimation of domain of attraction for closed-loop system, is transformed into a convex optimization issue with linear matrix inequalities (LMI) constraints. Finally, an example is given to verify the effectiveness of the proposed method. © 2022 Chinese Automatic Control Society and John Wiley & Sons Australia, Ltd.

Saccharina japonica polysaccharides exhibit great potential to be developed as anti-obesity and prebiotic health products, but the underlying mechanism has not been adequately addressed. In this study, we investigated the potential mechanism of a S. japonica polysaccharide fraction (SjC) in preventing high-fat-diet (HFD)-induced obesity in mice using 16S rRNA gene and shotgun metagenomic sequencing analysis. SjC was characterized as a 756 kDa sulfated polysaccharide and 16 weeks of SjC supplementation significantly alleviated HFD-induced obesity, insulin resistance, and glucose metabolism disorders. The 16S rRNA and metagenomic sequencing analysis demonstrated that SjC supplementation prevented gut microbiota dysbiosis mainly by regulating the relative abundance of Desulfovibrio and Akkermansia. Metagenomic functional profiling demonstrated that SjC treatment predominantly suppressed the amino acid metabolism of gut microbiota. Linking of 16S rRNA genes with metagenome-assembled genomes indicated that SjC enriched at least 22 gut bacterial species with fucoidan-degrading potential including Desulfovibrio and Akkermansia, which showed significant correlations with bodyweight. In conclusion, our results suggest that SjC exhibits a promising potential as an anti-obesity health product and the interaction between SjC and fucoidan-degrading bacteria may be associated with its anti-obesity effect.

In recent years, non-uniformly geometrical nanopores, such as conical nanopores, have gained significant attention in nanopore sensing technology due to their advantages in analyte manipulation and clear output signals. This paper focuses on the polymer translocation through a sandglass-like nanopore, characterized by a double-conical geometry with a tip at the middle. We systematically investigate the effects of pore geometry on the translocation dynamics through computational simulations and theoretical analyses. The polymer translocation process is divided into three stages: approaching, threading, escaping, corresponding to the movement from the entry to the tip, through the tip, and from the tip to the exit, respectively. Our findings reveal that the duration of the approaching stage highly depends on the polymer conformations, while the durations of the threading and escaping stages are primarily influenced by the driving force associated with the pore geometry and the accompanying free energy change. Additionally, we report a relationship between the threading speed of the polymer at the tip and the combination of the driving force there and the free energy change during the threading stage. © 2023 Wiley Periodicals LLC.

A sulfated galactofucan designated as UpG was obtained from the brown algae Undaria pinnatifida by calcium chloride extraction. Chemical analyses showed that UpG is composed of galactose and fucose at a high sulfation level. Low-molecular weight UpGP-0.5 was prepared from UpG through acid hydrolysis for structure characterization. The backbones of UpG are determined to be alpha-(1,3)-Fuc, alpha-(1,4)-Gal, alpha-(1,3)-Gal, and alpha-(1,6)-Gal by GC-MS, FT-IR, NMR, and LC-MS analyses. Sulfate groups are modified at C2 and/or C4 of fucose and C3 and/or C4 of galactose. UpG could partially lower blood sugar and serum lipid levels in type 2 diabetic mice. Moreover, UpG treatment regulates the abundance of some specific gut microbiota, such as enriching the abundance of Muribaculum and Christensenellaceae, and reducing that of Bilophila, Tannerellaceae, Candidatus Saccharimonas and Anaerotruncus. The findings characterized the detailed structure of a sulfated galactofucan and investigated its potential for the treatment of type 2 diabetes mellitus.

One of the challenges associated with the treatment of Pseudomonas aeruginosa infections is the high prevalence of multidrug resistance (MDR). Since conventional antibiotics are ineffective at treating such bacterial infections, innovative antibiotics acting upon novel targets or via mechanisms are urgently required. In this study, we identified a quorum sensing inhibitor (QSI), norharmane, that uniquely shows weak anti-bacterial activity but strongly inhibits pyocyanin production and biofilm formation of MDR P. aeruginosa. Biophysical experiments and molecular docking studies showed that norharmane competes with anthraniloyl-AMP for anthranilyl-CoA synthetase PqsA of P. aeruginosa at the ligand-binding pocket, which is not exploited by current inhibitors, thereby altering transcription regulatory activity. Moreover, norharmane exhibits synergy with polymyxin B. This synergism exhibits a high killing rate, low probability of resistance selection, and minimal cytotoxicity. Notably, norharmane can effectively boost polymyxin B activity against MDR P. aeruginosa-associated infections in animal models. Together, our findings provide novel insight critical to the design of improved PqsA inhibitors, and an effective combination strategy to overcome multiantibiotic bacterial resistance using conventional antibiotics and QSIs.IMPORTANCE Pseudomonas aeruginosa is a dominant hospital-acquired bacterial pathogen typically found in immunocompromised individuals. It is particularly dangerous for patients with chronic lung diseases and was identified as a serious threat for patients in the 2019 Antimicrobial Resistance Threats report (https://www.cdc.gov/drugresistance/biggest-threats .html). In this study, we used activity-based high-throughput screening to identify norharmane, a potent and selective inhibitor of P. aeruginosa PqsA, which is a well-conserved master quorum sensing (QS) regulator in multidrug resistant (MDR) P. aeruginosa. This compound competitively binds anthranilyl-CoA synthetase PqsA at the anthraniloyl-AMP binding domain, which has not been exploited by known inhibitors. Remarkably, norharmane can significantly block the production of the virulence factor, pyocyanin (87%), and biofilm formation (80%) in MDR P. aeruginosa. Furthermore, norharmane is capable of augmenting polymyxin B activity against MDR P. aeruginosa in cell cultures and animal models. Taken together, these results suggest that norharmane may be an effective adjuvant for combating multiantibiotic bacterial resistance.